Cystic fibrosis (CF), the most common lethal autosomal genetic disorder in the Caucasian population, occurs approximately once in every 2500 live births (Boat, et al., The Metabolic Basis of Inherited Disease, eds. Shriver, et al., McGraw-Hill, New York (1989) pp. 2649-2680). A single locus for CF has been mapped to chromosome 7q31 by linkage analysis using DNA marker probes.
Several markers have been shown to have a high degree of linkage disequilibrium with the CF locus in Caucasians suggesting that one mutation of the CF gene predominates in this population (Estivill, et al., Nature, (1987), 326:840; Estivill, et al., Genomics, (1987), 1:257). DNA polymorphism haplotypes from phenotypically and racially diverse patient populations indicated that several additional mutations of the CF gene may exist in these groups (Ober, et al., Am. J. Hum. Genet., vol. 41, p. 1145, 1987; Estivill, et al., ibid., vol. 43, p. 23 (1988); Fujiwara, et al., ibid., vol. 44, p. 327, (1989); Kerem, et al., ibid. p. 827 and Cutting, et al., ibid., p. 307).
The gene responsible for CF has recently been identified (Rommens, et al., Science, vol. 245, p. 1059 (1989); Riordan, et al., ibid., p. 1066); it comprises 20 exons and encodes a protein of 1480 amine acids called the CF Transmembrane Conductance Regulator (CFTR). Several regions are postulated to have functional importance in the CFTR protein, including two areas for ATP binding, termed Nucleotide Binding Folds (NBF), a Regulatory (R) region that has multiple potential sites for phosphorylation by protein kinases A and C, and two hydrophobic regions believed to interact with cell membranes.
One mutation has been identified in the CF gene which leads to the omission of phenylalanine residue 508 within the first putative NBF domain, indicating that this region is functionally important. This mutation, termed .DELTA.F.sub.508, accounts for about 70% of the CF chromosomes in Caucasian patients and was highly associated with the predominant haplotype found on chromosomes of Caucasian CF patients (Kerem, et al., Science, vol. 245, p. 1073 (1989); Lemna, et al., New Engl. J. Med., vol. 322, p. 291 (1990)); the haplotypes associated with Caucasian CF chromosomes without .DELTA.F508 are less common, confirming predictions that allelic heterogeneity exists in CF (Ober, et al., Am. J. Hum. Genet., vol. 41, p. 1145, 1987; Estivill, et al., ibid., vol. 43, p. 23 (1988); Fujiwara, et al., ibid., vol. 44, p. 327, (1989); Kerem, et al., ibid. p. 827 and Cutting, et al., ibid., p. 307; Kerem, et al., Science, vol. 245, p. 1073 (19S9)).
There is a need in the art of genetic screening for knowledge of other mutant alleles of CFTR which are present on the other 30% of CF chromosomes in Caucasian CF patients, as well as other alleles found in other racial groups. Knowledge of such alleles can be used to design probes for screening, as well as to devise other screening methods. The more complete the set of probes available for CF mutant alleles, the more accurate diagnoses can be made.